REVIEW ARTICLE
The Scourge of Antibiotic Resistance: The
Important Role of the Environment
Rita L. Finley,1 Peter Collignon,2 D. G. Joakim Larsson,3 Scott A. McEwen,4 Xian-Zhi Li,5 William H. Gaze,6
Richard Reid-Smith,7 Mohammed Timinouni,8 David W. Graham,9 and Edward Topp10
1
Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance
in human pathogens having originated in bacteria from the natural environment (eg, β-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of “new” antibiotic resistance genes
has been enhanced by modern human activity and its influence on the environmental resistome. This highlights
the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil
and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes
in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and
animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.
Keywords. antibiotic resistance; environment; human resistant infections.
Resistant infections are becoming more difficult or
even impossible to treat with current antibiotics, leading
to infections causing higher morbidity and mortality,
imposing huge costs on our society [1, 2]. This increasing resistance involves many common human pathogens, including Enterococcus faecium, Escherichia coli,
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and other
Enterobacter species [2, 3]. However, many of these
bacteria and/or their modes of resistance came from
Received 18 January 2013; accepted 15 May 2013; electronically published 30
May 2013.
Correspondence: Rita Finley, MSc, Centre for Food-borne, Environmental and
Zoonotic Infectious Diseases, Public Health Agency of Canada, 255 Woodlawn
Road Unit 120, Guelph, ON, N1H 8J1, Canada (rita.finley@phac-aspc.gc.ca).
Clinical Infectious Diseases 2013;57(5):704–10
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/cit355
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the natural environment, including bacteria within soils
and water. Antibiotic resistance development is not just
a local public health issue but includes broader environmental influences, which are amplified by international travel and global trade in foodstuffs.
The World Health Organization (WHO) recently announced a suite of policies that, if implemented, should
mitigate the emergence and further dissemination of
antibiotic-resistant organisms [4]. These initiatives have
focused on antibiotic stewardship in the hospital and community settings, and reducing antibiotic use in livestock
production. However, if we are to better manage antibiotic resistance, it is also vital that we consider the broader
environment. Therefore, an improved understanding of
the impacts of human activities on antibiotic resistance
development is needed, such as nonhuman antibiotic
use, pharmaceutical manufacturing waste, domestic and
agricultural waste releases into the environment, and the
influence of poor sanitation and unsafe water supplies.
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Centre for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Guelph, Ontario; 2Infectious Diseases Unit and
Microbiology Department, The Canberra Hospital and Canberra Clinical School, Australian National University; 3Department of Infectious Diseases,
Institute of Biomedicine, University of Gothenburg, Sweden; 4Department of Population Medicine, Ontario Veterinary College, University of Guelph,
Canada, 5Veterinary Drugs Directorate, Health Canada, Ottawa, Ontario; 6European Centre for Environment and Human Health, Exeter University Medical
School, Knowledge Spa, Royal Cornwall Hospital, Truro, United Kingdom; 7Laboratory for Foodborne Zoonoses, Public Health Agency of Canada, Guelph,
Ontario; 8Molecular Bacteriology Laboratory, Pasteur Institute of Morocco, Casablanca; 9School of Civil Engineering and Geosciences, Newcastle
University, United Kingdom; and 10Agriculture and Agri-Food Canada, London, Ontario
ANTIBIOTIC RESISTANCE GENES ARE
UBIQUITOUS AND ANCIENT
Our world is inhabited by approximately 5 × 1030 bacteria, the
vast majority of which are not pathogenic. Through evolutionary time, microorganisms developed capabilities for the biosynthesis of chemicals toxic to bacteria, “antibiotics,” which vary
widely in chemical structures, mode of action, and spectrum of
activity. This was paralleled by the development of strategies to
defeat antibiotics. Environmental bacteria, which predate the
modern antibiotic era by billions of years, carry genes encoding
resistance to antibiotics that have become critically important
in medicine [10]. However, because only approximately 1% of
environmental strains are culturable [11, 12], our knowledge of
the true diversity and composition of the environmental resistome is limited.
The ability to quantitatively link the transfer of specific resistance genes from environmental strains to human pathogens has
been difficult and, grossly underappreciated, although the ancient
nature of environmental resistance is clear [5]. For example,
viable multidrug-resistant bacteria were cultured from the Lechuguilla Cave in New Mexico even though it has been totally isolated
for >4 million years [12]. These bacteria were resistant to at least
1 antibiotic and often 7–8 antibiotics, including β-lactams, aminoglycosides, and macrolides, as well as newer drugs such as daptomycin, linezolid, telithromycin, and tigecycline. Two distinct
new macrolide inactivation mechanisms were identified, suggesting
that the utilization of the environmental microbiome could be
used to help combat resistance through the development of novel
antibiotics designed not to be inactivated by these mechanisms.
Likewise, DNA extracted from 30 000-year-old Beringian
permafrost contained genes coding for resistance to β-lactams,
tetracyclines, and glycopeptides, confirming that resistance predates antibiotic use in medicine and agriculture [10]. Furthermore, major β-lactamase classes predate the existence of humans.
Class A β-lactamases evolved approximately 2.4 billion years
ago and were horizontally transferred into the gram-positive
bacteria about 800 million years ago. The family of genes, including the progenitors of CTX-Ms, diverged 200–300 million
years ago [13]. Overall, these studies provide compelling evidence of the breadth of the resistome in environmental strains
and the intrinsic capacity for all bacteria to gain resistance.
Why are genes that confer resistance to antibiotics at clinically relevant concentrations ubiquitous? One explanation is that
bacteria that produce antibiotics must be resistant to them to
avoid self-destruction. In a highly diverse and competitive microbial environment such as soil, antibiotic-resistant bacteria
will have a competitive advantage against susceptible bacteria.
In addition, antibiotics are products of secondary metabolism,
and some have important physiological functions at different
concentrations, including the regulation of gene expression and
communication between bacteria [14]. Antibiotics at sublethal
concentrations can promote genetic exchanges through multiple pathways involving various stress responses [15]. Frequency
of transfer of tetracycline-resistance plasmids in S. aureus was
increased by up to 1000-fold in the presence of subinhibitory
concentrations of β-lactams [14, 16]. Also, antibiotics in animal
feed induced prophages in swine fecal microbiomes and contributed to phage-mediated resistance gene transfer [17], highlighting multiple environmental vectors for the horizontal
transfer of resistance genes. Finally, many bacteria, while also
resistant to multiple antibiotics, can actually use antibiotics as
their sole carbon source [18]. Overall, the ancient origin of
resistance genes highlights the need to take effective measures
to control antibiotic usage in people and animals, the major
drivers for the modern emergence of resistance. Indeed, in
Australia, low levels of resistance to fluoroquinolones in key
pathogens have resulted from restricted quinolone use in
humans and absent use in food animals [19].
HUMAN ACTIVITY IS ENHANCING THE
ENVIRONMENTAL RESISTOME
Human activity since the industrialization of antibiotic production after World War II has changed the distribution and increased the abundance of resistance genes. Genes encoding
resistance were 2–15 times more abundant in 2008 compared
to the 1970s in DNA extracted from archived soil samples collected between 1940 and 2008 in the Netherlands [20]. In
particular, genes encoding resistance to β-lactams and tetracyclines were enriched. Worrisomely, an increase in extended
spectrum β-lactamases (ESBLs) of the CTX-M family was observed, which appears to predate any clinical detection of these
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There are emerging concerns that anthropogenic impacts are
changing environmental reservoirs of resistance genes, “the resistome” [5], which will increase the probability of recruitment
of resistance genes into clinically relevant pathogens [6]. For
example, wastewater treatment, drug manufacturing, and agricultural effluents release massive quantities of antibiotic residues and resistant bacteria, selected in the digestive tracts of
people or animals by antibiotic use [7].
Exposure of environmental bacteria to antibiotics as well as
to large numbers of resistant bacteria may accelerate the evolution of resistance, increase the abundance and distribution of
resistance genes within the resistome that is critical to the development of clinical resistance, and increase exchange of antibiotic resistance genes between bacteria [8, 9]. People and
animals are connected to each other through the environment,
and it is important to consider antibiotic resistance within the
“One Health” concept, which provides a global strategy for expanding interdisciplinary collaboration and communication.
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concentrations of antibiotics lead to selection for antibiotic resistance [45]. Antibiotic concentrations in untreated hospital
effluents are lower, but still in the microgram per liter
range [46]. Wastewater treatment and hospital effluents are
therefore potential “hot spots” for the enrichment and transmission of resistant bacteria [42].
We also release large numbers of resistant bacteria that have
multiplied exponentially in the gastrointestinal tracts of people
and animals treated with antibiotics. These bacteria, in agricultural and wastewater effluents, harbor resistance genes and
genetic elements that promote their exchange between bacteria
[47, 48]. Commensals as well as pathogens are important
sources of resistance genes that can be shared, eventually
leading to human infections and disease [49]. Indirect selection
for antibiotic resistance also needs to be considered. Resistance
mechanisms to biocides or heavy metals may be present on the
same genetic elements as those conferring resistance to antibiotics [50], causing cross-resistance.
Antibiotic resistance can be acquired through mutation of
existing DNA, uptake of foreign DNA by means of transformation or phage-mediated transduction, and/or by conjugation
(DNA exchange directly from other bacteria). Transposition of
DNA within genomes also plays an important role in the mobilization of resistance determinants. Horizontal gene transfer is
highly important in the evolution and transmission of resistance genes between species and includes the movement of resistance genes from fecal bacteria to environmental bacteria, as
well as the reverse; that is, emergence of novel mechanisms of
acquired resistance in pathogens, genes that originally were
present in harmless bacteria [51]. Transduction has been identified to be important in the exchange of these genes with other
organisms, particularly in freshwater [52]. Taken together,
these anthropogenic inputs have increased reservoirs of resistant bacteria, including significant acquired resistance in pathogenic strains [51].
There is an interrelationship between humans, animals, and
the environment. Both methicillin-resistant S. aureus (MRSA)
and ESBL-producing E. coli can be used as indicators to evaluate
the movement of resistant bacteria in the environment [53].
ESBL-producing bacteria cause serious infections around the
world and can be recovered from foods for human consumption
as well as in wildlife [53–55]. However, only after ESBL-producing
E. coli appeared in livestock was this organism then identified
in wildlife, suggesting that ESBL-producing E. coli is likely disseminated via manure applications [53]. Similarly, genes responsible for MRSA (mecA) have rarely been reported in isolates
from aquatic environments. However, a mecA gene was recently
identified from phage DNA isolated from waste and natural
water, although its presence did not correlate with fecal contamination [56]. The emergence of novel MRSA strains in animals
and the multiple methicillin resistance gene transfer events that
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enzymes. Furthermore, since industrialization, millions of tons
of antibiotics have been released into the environment, including via wastewater effluents, land application of animal wastes,
treatment of crop diseases, aquaculture, and many other activities. For example, 71% of total Danish antibiotic consumption
(kg) in 2010 was for animal production [21]. A similar trend of
antibiotic use in humans vs animals was also observed in
Canada [22].
Public health impacts from antibiotic use in agriculture and
aquaculture have already drawn much attention in the last
decade [23–26]. Importantly, antibiotics used in humans and
animals often belong to the same classes. The WHO has established a list of “critically important” antibiotics in humans to
ensure prudent drug use in both human and veterinary medicine [26]. The third- and fourth-generation cephalosporins, fluoroquinolones, and macrolides are considered the drugs most
urgently requiring risk management of their use in food
animals. The use of extra-label third-generation cephalosporins
poses an important challenge [27–30]. A comparison of ESBLproducing E. coli from retail chicken meat and humans has
shown significant genetic similarities with respect to mobile
resistance elements, virulence genes, and genomic backbone
[31, 32]. The relationship between antibiotic use and resistance
is exemplified in a novel manner by recent work on the longterm exposure of tetracyclines on honeybees, which showed the
accumulation of mobile tetracycline resistance genes closely
related to those from human pathogens in the gut microbiota
of bees [33].
Antibiotic use in large-scale industrial agricultural facilities,
which raise food animals at high-density, highlight many
public health impacts including increased resistance and decreased water quality [34–36]. Similarly, impacts from largescale and widespread antibiotic use in aquaculture need to be
addressed [20, 37]. Specifically, fish infections are treated
through the administration of antibiotics directly into the
water, avoiding any kind of purification processes [38]. Aquaculture is increasingly important because fish production has
increased substantially over the last 50 years with 52.5 million
tons processed in 2008 [39].
Many antibiotics are excreted unchanged, are environmentally persistent, and can be detected downstream of wastewater
treatment plants and adjacent to fields receiving animal
manures [40]. In treated effluents and sewage sludge, antibiotic
residues of several classes range in concentrations from nanograms per liter up to low micrograms per liter [41]. Although
these are well below minimum inhibitory concentrations
(MICs), even low concentrations provide selective advantages
for certain resistant strains [42].
Concentrations well above MICs (milligram per liter range)
have been found in treated wastewater from drug manufacturing [43, 44]. Environments contaminated with such high
EVIDENCE THAT HUMAN PATHOGENS HAVE
ACQUIRED RESISTANCE GENES FROM
ENVIRONMENTAL BACTERIA
There are 2 types of evidence that show human pathogens have
acquired resistance genes from environmental bacteria. These
are phylogenetic evidence (analyses of gene sequences and their
context, revealing historic signatures of resistance determinants), and direct epidemiologic evidence from locations with
less than adequate sanitation, especially poor drinking water
quality.
The origins for some of the most common and problematic
resistance genes are aquatic organisms such as Shewanella
species, which carries a gene encoding quinolone resistance
genes (qnr) on its chromosome [62]. In humans, plasmid borne
qnr genes are more commonly identified in strains from Enterobacteriaceae infections, particularly E. coli and Salmonella.
However, in the natural environment, this gene is mainly found
in waterborne species, such as Aeromonas species and Citrobacter species, and in the Vibrionaceae family [62].
The origin of CTX-Ms was in Kluyvera species although it
is unknown whether mobilization of the progenitor genes
occurred in the environment or within the human microbiome [63]. Kluyvera has been recovered from water, soil,
sewage, hospital sinks, and food of animal origin [64], but rarely
from human clinical infections. However, even more resistance
genes have now been identified, such as KLUC-1, a chromosomal β-lactamase found in Kluyvera cryocrescens. Although many of
these have yet to be identified in clinical cases, they represent a
reservoir for new potential clinical ESBLs [52].
WATER AS A DISSEMINATION ROUTE FOR
RESISTANCE
Bacteria do not live in isolation, but are readily dispersed
through the world by humans, animals, plants, soil, water, and
air. An underappreciated exposure route for the dissemination
of antibiotic resistance is water, and multidrug-resistant bacteria have been detected from various water sources, including
drinking water. This is a major concern in developing countries
and has been a major route for the transmission of pathogenic
bacteria to people in developed countries in the past [48, 52,
65, 66]. Consumption or handling of water, whether treated or
not, can lead to the colonization of the gastrointestinal tract in
humans [67] and animals with bacteria containing resistance
genes. This in turn, can result in exchange of genes with bacteria (commensal or pathogenic) already present in the human/
animal gut. In addition, water is used for the irrigation of
plants for animal and human consumption, contaminating
products that could also lead to human/animal colonization
with antibiotic-resistant organisms.
Freshwater is an important vehicle for the spread and emergence of antibiotic resistance [52]. Recently, the New Delhi
metallo-β-lactamase-1 (NDM-1) genes were shown to be widely
disseminated in many different bacterial species in water
sources. Of more concern was the high prevalence of NDM-1
genes in bacteria in chlorinated municipal drinking water
samples in India [68]. These NDM-1 genes were identified
among 11 new species including Shigella boydii, Vibrio cholera,
and Aeromonas caviae. The transfer of NDM-1 genes to E. coli,
Salmonella Enteritidis, and Shigella sonnei was optimal at 30°C,
the average daily peak temperature between April to October in
that area of India. This specific gene is of great public health
concern because it confers resistance to all β-lactams, including
carbapenems, and coexists on gene transfer vectors with many
other resistance determinants [68]. This means that with the
rapid and simultaneous transmission of resistance can occur to
almost all clinically important antibiotics [68].
Coastal waters also comprise a potential exposure route of resistant bacteria via contamination with wastewater. Based on
WHO risk assessments, Shuval et al estimated that globally
there are in excess of 120 million cases of gastrointestinal disease
from exposure to coastal waters via recreation or by eating raw
or lightly cooked shellfish [69]. This in itself is not proof of mobilization of resistant bacteria from environment to clinic, but it
illustrates the scale of direct human exposure to contaminated
water. Preliminary data from Gaze et al (written communication, November 2011) suggest that in some UK bathing waters,
CTX-M carriage in enteric bacteria may be as high as 0.1%.
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have occurred in these strains point to the powerful selective
pressure exerted by antibiotic use in farming [57].
The rapid emergence of infections associated with multidrug
resistance in Acinetobacter species has been increasingly observed globally. In the 1970s–1980s, Acinetobacter, a gram-negative organism commonly found in soil and water, was often
susceptible to antibiotics. Today, Acinetobacter is one of the
most difficult resistant gram-negative bacteria to control and
treat [58]. Outbreaks have been associated with contamination
of the hospital environment and equipment with multidrugresistant strains introduced into hospitals by returning soldiers [59] and earthquake survivors [60]. Multidrug-resistant
A. baumannii possesses almost all typical mechanisms of resistance (eg, multiple β-lactamases including carbapenamases,
aminoglycoside-modifying enzymes, and drug efflux pumps)
that render the organism resistant to almost all classes of antibiotics. Resistance islands in the chromosome of A. baumannii
have large numbers of resistance genes and mobile genetic elements, and explains the sophisticated mechanisms of resistance
in this species [61]. Most of these resistance genes have likely
been acquired from Pseudomonas, Salmonella, or E. coli [61],
probably mediated by environmental reservoirs.
any residual antibiotic present in animal manure, as well as the
need for better rearing methods for fish to decrease the levels of
disease and the need for regulations and monitoring for antibiotic use in aquaculture [72]. In addition, several recommendations were made for the removal of antibiotics or antibiotic
resistance genes present at wastewater treatment plants, looking
at different components of the water cleaning process as critical
control points. Nevertheless, increasing antibiotic resistance
will not be reversed only by removing selective pressure. The
rate of resistance acquisition from intrinsic sources must be
reduced, especially to human pathogens, and this can only be
done through much greater consideration of the natural environment in resistance transmission. A One Health approach is
clearly needed to address all the different contributions that
assist in the development and dissemination of antimicrobialresistant organisms. Having all the sectors working independently is not sufficient; communications and collaborations
must be strengthened to be effective and have an impact.
CONCLUSIONS
Notes
The bacterial metagenome is vast and bacteria are promiscuous. Rare gene transfer events can be clinically significant, but
this vastness makes it very difficult to pinpoint when and where
gene transfer events have led to acquired resistance in human
pathogens and, in turn, demonstrate causality. However, our
expanding understanding of the ancient origin and modern
evolution of antibiotic resistance genes have demonstrated the
important role of the environment in both the emergence and
spread of resistance. Various human activities have contributed
to the rapid evolution of antibiotic resistance since the start of
the antibiotic era.
Resistant organisms disseminate from humans to animals,
and vice versa, often through various environmental pathways,
including foodstuffs, animal wastes, and water sources. However, although food products may have the established maximum antibiotic residue limits, there is no threshold guidance
regarding the presence of resistant bacteria or resistance determinants in water sources. Current water quality guidelines tend
to focus only on specific bacteria, but do not have appropriate
guidance for the presence of antibiotics introduced by manufacturers, domestic disposal, agriculture, and/or the medical
sector. In addition, other environmental sources of antibiotics
and resistance genes, such as human and agricultural wastes,
lack strong guidance, particularly for risk management. Therefore, new guidance is needed and actions taken to reduce selection pressures in natural and farmed/aquaculture environments
and also to reduce human exposure rates to resistant strains. A
priority should include risk management to minimize antibiotic residues and resistant bacteria in intensive animal facilities as
well as from aquaculture. Pruden et al have recommended the
use of composting and manure digestion for the degradation of
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Financial support. This manuscript was conceived at the Antimicrobial
Resistance in the Environment: Assessing and Managing Effects of Anthropogenic Activities workshop, held in Montebello, Québec, Canada, on 4–8
March 2012. The workshop was sponsored by the Canadian Society of Microbiologists with financial support from AstraZeneca, Pfizer Animal
Health, F. Hoffman-La Roche, GlaxoSmithKline, Unilever, Huvepharma,
the American Cleaning Institute, the Canadian Animal Health Institute, the
German Federal Ministry for the Environment, Nature Conservation and
Nuclear Safety, Health Canada, and the Public Health Agency of Canada.
D. G. J. L. has received institutional grant funding from the Swedish Research Council, and W. H. G. received institutional funding to travel to the
meeting from the Canadian Society of Microbiology.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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